Central effects of the preservative, methylparaben. In vivo activation of cAMP-specific phosphodiesterase and reduction of cortical cAMP
Date
1992
Authors
Harvey B.H.
Carstens M.E.
Taljaard J.J.F.
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Abstract
The phenolic preservative, methylparaben (MPB), has in the past been demonstrated to harbour definite pharmacological effects. In an attempt to examine the possible central effects of MPB, notably on cyclic nucleotides and cyclic nucleotide phosphodiesterase (PDE; EC 3.1.4.17), rats were orally treated with the drug (0.4% in rat food) for 3 weeks with cortex extracts being used for the various determinations. Three isozymes were identified by DEAE-cellulose anion exchange chromatography, namely the calmodulin/calcium-stimulated form or PDE I (peak I), the cGMP-stimulated form or PDE II (peak II), and an independent form not affected by either calmodulin or cGMP also known as PDE IV (peak III). The presence of MPB induced a significant decrease in cortical cAMP, as well as strongly stimulating the activity of PDE IV (peak III). In addition, a small, yet significant, increase in cGMP levels was observed. Since no increase in cGMP hydrolysis was observed, we conclude that chronic ingestion of MPB induces a preference for cAMP hydrolysis, which was confirmed by the increase in PDE IV (peak III) activity. PDE IV is a membrane-bound, low K(m) PDE exhibiting high selectivity for cAMP hydrolysis. While there was an increase in cGMP, we failed to observe an increase in the activity of the cGMP-stimulated PDE (PDE II). These data are discussed with reference to the possible membrane effects of MPB allowing it to alter both the kinetic properties of PDE IV with the resultant effects on cAMP, as well as a means whereby it may activate guanyl cyclase and increase cGMP.
Description
Keywords
calmodulin, cyclic amp, cyclic amp phosphodiesterase, cyclic gmp, cyclic gmp phosphodiesterase, cyclic nucleotide, cyclic nucleotide phosphodiesterase, isoenzyme, methyl paraben, preservative, animal tissue, anion exchange chromatography, article, brain cortex, controlled study, enzyme activity, hydrolysis, male, neurochemistry, nonhuman, oral drug administration, priority journal, rat, 3',5'-Cyclic-Nucleotide Phosphodiesterase, Animal, Cerebral Cortex, Cyclic AMP, Cyclic GMP, Down-Regulation, Enzyme Activation, Isoenzymes, Male, Parabens, Rats, Rats, Wistar, Support, Non-U.S. Gov't
Citation
Biochemical Pharmacology
44
6
44
6